Engineered Antibody Precisely Targets Mutant HER2 in Cancer Cells
Key Insights
Researchers at NYU Langone Health have developed an antibody that selectively targets the mutated form of HER2 (search), a protein implicated in aggressive cancers.
The antibody was engineered using advanced protein-engineering techniques to distinguish between normal and mutant HER2 (search) proteins.
The engineered antibody was fused with another one that grabs onto T cells, creating bispecific T cell engager, which effectively kills cancer (search) cells in lab tests.
Researchers at NYU Langone Health's Perlmutter Cancer (search) Center have engineered a novel antibody capable of distinguishing between normal HER2 (search) protein and its mutated form, which drives the growth of certain aggressive cancers. This breakthrough could lead to more precise cancer therapies that eliminate cancer cells while sparing healthy ones.
Targeting the 'Always-On' Mutation in HER2
HER2 (search), or human epidermal growth factor receptor 2, is a protein that regulates cell growth and division. However, a single amino acid mutation can lock HER2 into an "always-on" state, leading to uncontrolled cell division and cancer (search). While existing drugs like trastuzumab and pertuzumab target HER2, they can harm healthy cells, resulting in significant side effects.
Shohei Koide, PhD, a professor at NYU Grossman School of Medicine and a lead author on the study, stated, "We set out to do something people said was nearly impossible. We wanted to create an antibody that could recognize a single difference in the 600 amino acids that make up the HER2 (search) protein. To be honest, we were surprised by how well it worked."
Engineering a Selective Antibody
The team employed advanced protein-engineering techniques to develop antibodies that selectively bind to the mutant HER2 (search) protein. This involved exposing antibodies to multiple rounds of mutation and selection, refining them to recognize only the mutant version.
Bispecific T Cell Engager for Enhanced Efficacy
To enhance the antibody's efficacy, the researchers created a bispecific T cell engager by fusing the HER2 (search)-targeting antibody with another antibody that binds to T cells. This approach recruits the immune system to kill cancer (search) cells expressing the mutant HER2 protein.
Promising Preclinical Results
In lab tests, the bispecific T cell engager effectively killed cancer (search) cells with mutant HER2 (search) while sparing those with the normal protein. When tested in mice with tumors (search), the treatment shrank the tumors without causing typical side effects like weight loss or sickness.
Cautious Optimism
While the preclinical results are promising, researchers caution that differences between mouse and human proteins could affect the translation of these findings to human patients. "We saw very few side effects in mice," Koide says, "but there are important differences between mouse and human proteins. It’s possible that the treatment had fewer side effects in mice because the antibody binds more weakly to mouse HER2 (search) than to human HER2."
The team is continuing to refine the antibody and explore its potential for targeting other cancer (search)-causing proteins. Their ultimate goal is to develop precision medicine approaches that target the root cause of cancer while minimizing harm to the rest of the body.